Treatment of cancer

Abstract

The present invention relates to improved treatment of cancer, in particular to a treatment with a composition of CTL peptides for patients after a treatment with an immune checkpoint inhibitor.

The invention claimed is: 
     
       1. A method of treating cancer in a Human Leukocyte Antigen A2 (HLA-A2) positive patient comprising administering, to a HLA-A2 positive patient having already been treated as a last treatment with an immune checkpoint inhibitor alone or in combination with another cancer therapy and has cancer progression after the last treatment, a peptide composition comprising aKXVAAWTLKAAa (SEQ ID NO: 10, with X and a, respectively, indicating cyclohexylalanine and d-alanine) and at least 4, 5, 6, 7, 8 or 9 peptides selected from the group consisting of RLLQETELV (SEQ ID NO: 1), YLQLVFGIEV (SEQ ID NO: 2), LLTFWNPPV (SEQ ID NO: 3), KVFGSLAFV (SEQ ID NO: 4), KLBPVQLWV (SEQ ID NO: 5, with B indicating α-aminoisobutyric acid), SMPPPGTRV (SEQ ID NO: 6), IMIGHLVGV (SEQ ID NO: 7), KVAEIVHFL (SEQ ID NO: 8), and YLSGADLNL (SEQ ID NO: 9) wherein the patient has a secondary resistance against the immune checkpoint inhibitor and wherein the secondary resistance is a loss of therapeutic efficiency after 3 months of treatment with the immune checkpoint inhibitor. 
     
     
       2. The method according to  claim 1 , wherein the peptide composition comprises the following peptides: aKXVAAWTLKAAa (SEQ ID NO: 10, with X and a respectively indicating cyclohexylalanine and d-alanine), RLLQETELV (SEQ ID NO: 1), YLQLVFGIEV (SEQ ID NO: 2), LLTFWNPPV (SEQ ID NO: 3), KVFGSLAFV (SEQ ID NO: 4), KLBPVQLWV (SEQ ID NO: 5, with B indicating α-aminoisobutyric acid), SMPPPGTRV (SEQ ID NO: 6), IMIGHLVGV (SEQ ID NO: 7), KVAEIVHFL (SEQ ID NO: 8), and YLSGADLNL (SEQ ID NO: 9). 
     
     
       3. The method according to  claim 1 , wherein the cancer is a cancer selected from the group consisting of NSCLC (non-small cell lung cancer), small cell lung cancer, melanoma, urothelial cancer, mesothelioma, breast cancers, primary brain cancers, glioblastoma, ovarian cancer, uterine carcinoma, uterine corpus and/or uterine cervix carcinoma, head and neck cancer, colorectal cancers, pancreatic cancer, gastric cancer, esophageal cancer, renal cancer, hepatocellular carcinoma, sarcoma, germ cell tumors, leukemia, lymphoma, Hodgkin's lymphoma, skin cancer, Merkel cell carcinoma, testicular cancer and bladder cancer. 
     
     
       4. The method according to  claim 1 , wherein the patient has an advanced cancer, optionally with metastasis. 
     
     
       5. The method according to  claim 4 , wherein the advanced cancer is a stage III, stage IIIA, stage IIIB, stage IIIc, or stage IV cancer. 
     
     
       6. The method according to  claim 1 , wherein the peptide composition is administered every one to four weeks, every two to three weeks, or every three weeks. 
     
     
       7. The method according to  claim 1 , wherein the peptide composition is administered at least twice or at least three times. 
     
     
       8. The method according to  claim 1 , wherein the peptide composition is administered one week to three months after cancer progression or two weeks to two months after cancer progression. 
     
     
       9. The method according to  claim 1 , wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor or an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor. 
     
     
       10. The method according to  claim 9 , wherein the IDO inhibitor is indoximod. 
     
     
       11. The method according to  claim 1 , wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, BMS936559, AMP-224, MEDI0680, avelumab, atezolizumab, durvalumab, tremelimumab and ipilimumab. 
     
     
       12. The method according to  claim 1 , wherein the immune checkpoint inhibitor is a PD-1 inhibitor. 
     
     
       13. A method of treating cancer in a Human Leukocyte Antigen A2 (HLA-A2) positive patient comprising administering, to a HLA-A2 positive patient having already been treated as a last treatment with a first immune checkpoint inhibitor alone or in combination with another cancer therapy and has cancer progression after the last treatment,
 a peptide composition comprising aKXVAAWTLKAAa (SEQ ID NO: 10, with X and a, respectively, indicating cyclohexylalanine and d-alanine) and at least 4, 5, 6, 7, 8 or 9 peptides selected from the group consisting of RLLQETELV (SEQ ID NO: 1), YLQLVFGIEV (SEQ ID NO: 2), LLTFWNPPV (SEQ ID NO: 3), KVFGSLAFV (SEQ ID NO: 4), KLBPVQLWV (SEQ ID NO: 5, with B indicating α-aminoisobutyric acid), SMPPPGTRV (SEQ ID NO: 6), IMIGHLVGV (SEQ ID NO: 7), KVAEIVHFL (SEQ ID NO: 8), and YLSGADLNL (SEQ ID NO: 9) and 
 a second immune checkpoint inhibitor to the patient, wherein said patient has cancer progression after administration of the peptide composition. 
 
     
     
       14. A method of treating cancer in an HLA-A2 positive patient, wherein the patient received an immune checkpoint inhibitor as a last treatment, alone or in combination with another cancer therapy, the method comprising
 a) administering a therapeutically effective amount of a peptide composition comprising the peptide aKXVAAWTLKAAa (SEQ ID NO: 10, with X and a respectively indicating cyclohexylalanine and d-alanine) and at least 4, 5, 6, 7, 8 or 9 peptides selected from the group consisting of RLLQETELV (SEQ ID NO: 1), YLQLVFGIEV (SEQ ID NO: 2), LLTFWNPPV (SEQ ID NO: 3), KVFGSLAFV (SEQ ID NO: 4), KLBPVQLWV (SEQ ID NO: 5, with B indicating α-aminoisobutyric acid), SMPPPGTRV (SEQ ID NO: 6), IMIGHLVGV (SEQ ID NO: 7), KVAEIVHFL (SEQ ID NO: 8), and YLSGADLNL (SEQ ID NO: 9); 
 b) administering a therapeutically effective amount of an immune checkpoint inhibitor when a cancer progression occurs with the treatment with the peptide composition; and 
 c) optionally administering a therapeutically effective amount of a peptide composition as defined herein; 
 
       wherein steps a), b) and c) are sequential and wherein steps b) and c) can be repeated as long as the patient has a therapeutic benefit from the sequential treatment. 
     
     
       15. The method according to  claim 14 , wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, an IDO inhibitor, or a combination thereof. 
     
     
       16. The method according to  claim 15 , wherein the IDO inhibitor is indoximod. 
     
     
       17. The method according to  claim 14 , wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, BMS936559, AMP-224, MEDI0680, avelumab, atezolizumab, durvalumab, tremelimumab and ipilimumab.